The aim of this program project is to identify the gene for familial amyotrophic lateral sclerosis (ALS) and develop a transgenic model so as to be able to study the disease process in motor neuron disorders and test treatment modalities. Familial ALS is a genetic model of ALS, which is a degenerative disorder affecting the upper and lower motor neuron. ALS results in progressive paralysis and death. The cause of ALS is presently unknown, nor is there a treatment that will alter the course of the disease. This project will bring together investigators that linked a gene for familial ALS to chromosome 21. Investigators in the two laboratories will study the mapping and identification of the ALS gene in two separate and non overlapping subsets of familial ALS families. The mapping resources available to both centers will be utilized and exchanged. Polymorphic markers will be developed to narrow the gene region between 1 to 3 centiMorgans by linkage analysis. Current polymorphic markers and other resources being developed to map chromosome 21 will allow physical mapping of this interval. Genes expressed in the spinal cord that map to this interval will be used as candidate genes. Once the FALS gene is identified, tissue of individuals affected with familial ALS will be examined for gene mutations. Simultaneously with the mapping studies we will concentrate on developing a transgenic mouse model that will have specific gene expression in motor neurons. A transgenic model of motor neuron disease will also be developed. when the familial ALS gene is isolated, these transgenic models will allow the study of the ALS disease process and provide a vehicle for the design of experimental treatment in motor neuron disorders.